This invention relates to inhibitors of the family tyrosine kinase, and particularly, inhibitors of Bruton""s Tyrosine Kinase (BTK).
Apoptosis is a common mode of eukaryotic cell death which is triggered by an inducible cascade of biochemical events leading to activation of endonucleases that cleave the nuclear DNA into oligonucleosomexe2x80x94length fragments. Several of the biochemical events that contribute to apoptotic cell death as well as both positive and negative regulators of apoptosis have recently been identified (Whyllie A., et al. (1980) Int. Rev. Cytol. 68, 251-305;
Steller H., (1995) Science 267, 1445-1449; Fraser, A., Evan, G. (1996) Cell 85, 781-784;
and Korsmeyer, S. J. (1995). Trends Genet. 11, 101-105). Apoptosis plays a pivotal role in the development and maintenance of a functional immune system by ensuring the timely self-destruction of autoreactive immature and mature lymphocytes as well as any emerging target neoplastic cells by cytotoxic T cells.
In addition to the beneficial effects associated with apoptosis, inappropriate apoptosis contributes to the pathogenesis and drug resistance of human leukemias and lymphomas (Cohen, J. J., et al. (1992) Annu. Rev. Immuol. 10, 267-293; Linette, G. P., Korsmeyer, S. J. (1994) Curr. Opin. Cell Biol. 6, 809-815; and Thompson, C. B. (1995) Science 367, 1456-1462). Thus, agents that are useful to modulate apoptosis are potentially useful as therapeutic agents for treating diseases in which inappropriate apoptosis is implicated. As a result, there is a considerable amount of ongoing research devoted to the identification of molecular regulators of apoptosis, and there is currently a need for novel agents (e.g. chemical or biological), and novel therapeutic methods, that are useful for modulating apoptosis. Such agents and methods may be useful for treating cancer (e.g. leukemias and lymphomas) or immune disorders in mammals. They may also be useful as pharmacological tools for use in in vitro or in vivo studies to enhance the understanding of the molecular basis of apoptosis (e.g. the pro-apoptotic versus the anti-apoptotic regulatory signal), as well as the pathogenesis of human lymphoid malignancies.
The invention provides inhibitors of Tec family tyrosine kinases, and particularly of BTK. The inhibitors of the invention are useful in the treatment of pathologic conditions involving cells expressing Tec family tyrosine kinaes, such as Tcells (Tec, Itk) and B cells (BTK).
The invention provides compounds of formula I: 
where:
R1 is (C1-C3)alkyl, (C3-C6)Cycloalkyl, phenyl, or NRaRb;
R2 is hydroxy, (C1-C6)alkoxy. (C1-C6)alkanoyloxy amino (C2-C5)alkoxy; hydroxy (C2-C5)alkoxy amino (C2-C5)alkanoxy; or hydroxy (C2-C5) alkanoxy;
R3 is cyano or (C1-C3)alkanoyl;
R4 is hydrogen, (C1-C3)alkyl; hydroxy (C2-C5)alkyl; or amino (C2-C5)alkyl;
R5 is aryl, or heteroaryl;
Ra and Rb are each independently hydrogen, or (C1-C3)alkyl; or Ra and Rb together with the nitrogen to which they are attached are pyrrolidino, piperidino, morpholino, or thiomorpholino;
wherein any aryl, or heteroaryl of R1 and R5 is optionally substituted with one or more (e.g. 1, 2, or 3) substituents independently selected from halo, nitro, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, (C1-C3)alkoxy, (C1-C3)alkyl, (C1-C3)alkanoyl, xe2x80x94S(O)2Rcor NRaRb; wherein Rc is (C1-C3)alkyl, or aryl
or a pharmaceutically acceptable salt thereof;
provided that if R5 is phenyl, the phenyl is substituted by xe2x80x94S(O)2Rc, or is substituted by halo and at least one other substituent.
The invention also provides a compound of formula II: 
where:
X is O, N, or S;
R1 is H, alkyl, carboxyl,
preferably C1-C3 alkyl or C1-C3 carboxyl; and
R2 is alkyl, preferably C1-C6 alkyl.
The compounds of the invention are designed to fit a composite binding pocket model of the BTK domain, having a molecular volume of less than the volumne of the binding pocket (e.g., less than about 600 xc3x853) and preferably a volume that approaches ⅔ the volume of the pocket, e.g., approximately 400 xc3x853. Most preferably, the inhibitors of the invention are designed to fill the space of the binding pocket and to interact with residues of the pocket for enhanced binding.
The invention also provides a pharmaceutical composition comprising an agent that inhibits or prevents the action of Bruton""s tyrosine kinase; and a pharmaceutically acceptable carrier.
The invention also provides a method to promote or induce apoptosis in a BTK expressing cell comprising contacting the cell with an agent that inhibits or prevents the action of BTK.
The invention also provides a method to treat a disease (pathologic condition) wherein BTK is implicated and inhibition of its action is desired comprising administering to a mammal in need of such treatment an effective amount of an agent that inhibits or prevents the action of BTK.
The invention also provides a method to lower the resistance of a BTK expressing cell to drug therapy comprising contacting the cell with an agent that inhibits or prevents the action of BTK.
The invention provides a BTK inhibitor for use in medical therapy (preferably for use in treating cancer or other BTK mediated diseases), as well as the use of a compound of formula I for the manufacture of a medicament for the treatment of a pathological condition or symptom in a mammal, such as a human, which is associated with BTK (e.g. cancer, such as a leukemia or a lymphoma).